Since the discovery of stable N-heterocyclic carbenes (NHCs), these complexes have found widespread use in catalysis, serving both as nucleophilic catalysts and as ligands in metal-mediated reactions. See, for example, Arduengo et al. (1991) J. Am. Chem. Soc. 113:361-363; Arduengo (1999) Acc. Chem. Res. 32:913-921; Bourissou et al. (2000) Chem. Rev. 100:39-92; and Herrmann & Köcher (1997) Angew. Chem., Int. Ed Engl. 36:2162-2187. See also Enders & Balensiefer (2004) Acc. Chem. Res. 37:534-541; Herrmann et al. (2001) Adv. Organomet. Chem. 48:1-69; Herrmann (2002) Angew. Chem. Int. Ed. 41:1290-1309; and Perry & Burgess (2003) Tetrahedron: Asymmetry 14:951-961.
A variety of heterocyclic frameworks have been employed in the preparation of NHCs, including four-, five- and six-membered rings, as represented by compounds 1 through 5). To date, most catalytic applications employ the five-membered analogs.
See, for example, the references cited above. For exceptions with 4- and 6-membered NHCs, see Despagnet-Ayoub & Grubbs (2004) J. Am. Chem. Soc. 126:10198-10199; Despagnet-Ayoub & Grubbs (2005) Organometallics 24:338-340; Alder et al. (1999) J. Chem. Commun. 241-242; Guillen et al. (2001) Tetrahedron: Asymmetry 12:2083-2086; and Bazinet et al. (2003) J. Am. Chem. Soc. 125:13314-13315.
NHC ligands are electronically similar to phosphines (see Herrmann & Köcher (1997) Angew. Chem., Int. Ed. Engl. 36:2162-2187; Lee & Hu (2004) Organometallics 23:976-983). Based on the widespread success of chiral phosphines in asymmetric catalysis (see Tang & Zhang (2004) Chem. Rev. 103:3029-3069), chiral NHCs have significant utility.
However, conventional heterocyclic carbenes suffer from one shared limitation: the nearly planar heterocyclic framework of these ligands constrains the spatial display of substituents bonded to the heterocyclic ring. As a consequence of the planarity (or near planarity) of these compounds, their successful application to asymmetric catalysis (i.e., ≧90% enantiomeric excess) remains limited. See, for example, Perry & Burgess (2003) Tetrahedron: Asymmetry 14:951-961.
In the patent literature, the synthesis and various applications of NHCs have been described. For examples that describe the synthesis and use of 5-membered NHCs, see Khasnis et al., WO9827064 and Millitzer et al., U.S. Patent Application Publication 2003/0149273. For examples that describe various NHC-containing olefin-metathesis catalysts, see Bell et al., U.S. Pat. No. 6,838,489, which describes catalysts generated using a thermally activated NHC precursor. See also Herrmann et al., U.S. Pat. No. 6,635,768, which describes alkylidene complexes of ruthenium-containing NHC ligands and their use as selective catalysts for olefin metathesis. Along the same lines, see, Herrmann et al., U.S. Pat. No. 6,787,620, and Herrmann et al., U.S. Pat. No. 6,552,139. For examples of NHC-metal complexes and their use in coupling reactions, see Lee et al., WO0166248.
There remains, however, a clear and unmet need for chiral NHCs that can be used as catalysts or ligands in asymmetric synthesis. The ability to synthesize, isolate, and prepare metal complexes of NHCs that possess a non-planar heterocyclic framework has significant utility toward this end.